Determination of glucose concentration in tissue

ABSTRACT

A method for determining and monitoring tissue glucose concentration, wherein a perfusion solution is conveyed as a liquid column through a microdialysis probe implanted in the tissue and is moved to a test cell preferably arranged outside the patient&#39;s body, the volumetric flow of the perfusion solution being reduced in its time average for the duration of the dialysis intervals (T 1 ) and the volume of the perfusion solution perfused through the microdialysis probe during each dialysis interval (T 1 ) being moved on in a consecutive transport interval (T 2 ) at a higher volumetric flow to the test cell and wherein the glucose content of the perfusion solution passing through the test cell is determined from continuously detected test signals, characterized in that before passing through the microdialysis probe the perfusion solution is mixed with glucose in order to set a predetermined initial concentration.

DESCRIPTION

The invention relates to a method and apparatus to determine and monitorthe concentration of tissue glucose as defined in the preambles of theindependent claims 1 and 17.

Methods of this kind are applicable foremost in human medicine, inparticular to monitor the blood sugar of diabetics. They are based onthe insight that the glucose content of the interstitial tissue fluid ishighly correlated, with little time delay, to the blood sugar level. Itis known to recover glucose by dialysis and then to determine theglucose content by enzymatic-amperometric measurements in anflow-through test cell. For that purpose a continuous flow of perfusateis made to pass along the dialysis membrane of the dialysis probe. Theyield so obtained depends essentially on the rate of perfusion and as arule is less than 30%. The measurement is commensurately inaccuratebecause interfering factors such as tissue movement and changes in bloodcirculation strongly affect the yield and hence the test signal.Lowering the perfusion rate will not help because entailing acorrespondingly higher dead time caused by the flow time between themicrodialysis probe and the test site. On the other hand, high rates offlow velocity do indeed lower the dead time. However the dialysis yieldrelative to a unit volume of perfusion solution decreases to the sameextent. Moreover a glucose gradient is formed in the tissue surroundingthe microdialysis probe on account of continuously withdrawing glucose.However long-term treatment of diabetics mandates reliable glucosemeasurements to dose insulin administrations as needed and, wheredesirable, automatically.

Based on the above, the objective of the invention is to create a methodand apparatus of the initially cited kinds which offer high reliabilityand accuracy as regards glucose determination.

The combinations of features stated in the patent claims 1 and 17 areproposed as solutions. Further advantageous implementations of theinvention are stated in the dependent claims.

The conventional continuous enrichment of the perfusion solution isreplaced in the invention by equalizing the liquid column, moved insegments with high yield through the microdialysis probe, and the tissueglucose content. Accordingly the invention proposes to reduce thetime-averaged volumetric flow of the perfusion solution for the durationof dialysis intervals and that the volume of perfusion solution perfusedduring each dialysis interval through the microdialysis probe shall bemoved on in an ensuing transport interval at a higher volumetric flow tothe test cell. The equalization of concentration taking place during thedialysis intervals averts continuous impoverishment of the tissue. Atthe same time, high signal strength is achieved because of the higheryield. The enriched partial volumes can be moved at a higher conveyanceflow and thus with a lesser dead time to the test cell.

In a preferred implementation of the invention, the perfusion solutionis mixed with glucose before being made to pass through themicrodialysis probe and a predetermined initial concentration is set,preferably within the physiological range. Using an initial solutionmixed with glucose leads to diffusion enrichment or impoverishment atthe dialysis membrane depending on the tissue glucose concentration.Accordingly a signal peak or a signal dip is observed in thetime-sequence of the test signals at the test cell. On the other handthe subsequent perfusion solution passing at a higher flow during thetransport intervals through the microdialysis probe essentially retainsits initial glucose concentration. Accordingly a base line reflectingthe initial glucose concentration is picked up during the subsequentflow through the cell.

Advantageously the volumetric flow of perfusion solution is so adjustedduring the transport intervals that the glucose content of the perfusionsolution changes less than 10%, preferably less than 5%, on account ofthe reduced duration of dialysis, when passing through the microdialysisprobe. On the other hand, in order to increase the accuracy ofmeasurement, the volumetric flow during the dialysis intervals should beadjusted in such manner that the glucose content of the perfusionsolution essentially matches the concentration of tissue glucose whenpassing through the microdialysis probe.

Advantageously a base line value is determined from the test signalspicked up at the test cell during the flow-through of the volume of theperfusion solution perfused at higher-volumetric flow, said base linevalue reflecting the initial glucose concentration and thereby allowingcontinuous signal correction for instance in the event of fluctuationsin test sensitivity.

Advantageously the peak test signals ascertained during the transportintervals at the test cell when crossed by the enriched liquid-columnsegments are evaluated with respect to their extreme value, hereaftercalled extremum/extrema, or of their integrated value, to determine thetissue glucose concentration.

Advantageously the tissue glucose concentration is determined in eachtransport interval from the ratio of the extremum to the base line valueof the test signal multiplied by the value of initial glucoseconcentration and where called for by a predetermined calibration value.This procedure allows constantly updated calibration of the glucose testvalues and compensating any signal drifts. In this manner spuriousmeasurements can be precluded that otherwise might arise from conveyancemalfunctions or interferences in the test cell.

Because of the peak-shaped signal sequence of the test signals, validitytesting is feasible in that the predetermined time between the extremaof the test signals will be monitored by the time between the transportintervals.

Advantageously again, the signal sequence of the test signals is usedfor validity-checking the ascertained glucose content, a peak beingexpected as a valid signal shape when comparing a concentration valuehigher than the initially set glucose concentration and a dip for alesser value of concentration. In this manner reliable, qualitativechecking of the measurements is possible. Another increase inreliability of measurement can be achieved in that the initial glucoseconcentration is set to a sugar deficiency value and in that when thetest signals undergo a dip in their sequence, a sugar-deficiency alarmis triggered. Moreover it is basically feasible to adjust the initialglucose concentration in phases alternatingly--for instance using avalve circuit--to a sugar deficiency value and an excess sugar value, analarm signal being emitted at a dip during the phase of adjusted sugardeficiency value and at a peak during the phase of adjusted excess sugarvalue.

Qualitative pattern recognition in the sequence of the test signals isimplemented in simple manner in that the extrema ascertained in the timebetween the transport intervals are compared with the particularassociated base line value, where a peak shall be recognized whencomparing an extremum larger than the base line value and a dip shall berecognized when comparing an extremum smaller than the base line value.

In another preferred implementation of the invention, the perfusionsolution is moved during the dialysis intervals always in several,time-separated conveyed batches through the microdialysis probe. Therebythe glucose-enriched segment of the liquid column is widened andcorrespondingly the diffusion decay will be reduced during the ensuingtransport interval.

When seeking high yield in the dialysis, advantageously a volume of theperfusion solution substantially corresponding to the volume of themicrodialysis probe is moved at each conveyed batch. Another improvementcan be achieved in this respect by so sizing the conveyance pausesbetween conveyed batches that the glucose content of theperfusion-solution volume instantaneously present in the microdialysisprobe shall substantially equal the tissue glucose concentration.

In an alternative to the batch-conveyance, the volumetric flow of theperfusion solution may be reduced to a constant value for the durationof the dialysis intervals.

The initially cited problem regarding the measurement apparatus issolved in that at least one glucose reservoir containing glucose in apredetermined initial concentration can be connected to the perfusateline. In order to ascertain whether the tissue glucose represents adeficiency or excess of sugar, two glucose reservoirs separatelyconnectable to the perfusate line may be used, each containing dissolvedglucose of a different concentration.

Advantageously the at least one glucose reservoir shall be connectablethrough a switching valve to the perfusate line to allow mixing theperfusion solution selectively at separate times and/or if called for ata different concentration to the perfusate line.

A defined batch-wise conveyance of the perfusion solution, which may beenriched with glucose, can be implemented by using a metering pumppreferably operated at intervals as the conveyor unit.

The invention is elucidated below in relation to an illustrativeembodiment which is schematically shown in the drawing.

FIG. 1 shows a microdialysis system to measure subcutaneous glucoseconcentration, and

FIG. 2 is a time plot of the volumetric flow of the perfusion solutionthrough the system of FIG. 1.

The method of the invention to subcutaneously measure tissue glucose isbased on the principle of microdialysis and can be carried out using themeasuring apparatus shown in FIG. 1. Essentially this measuringapparatus consists of a microdialysis probe 12 implantable into thepatient's subcutaneous fatty tissue 10, of an through-flow test cell 14located outside the patient's body and a signal-processing unit 16cooperating with the test cell 14. To withdraw a sample from the tissue10, a perfusion solution 18 is pumped out of a reservoir 20 through aperfusate line 21 as a continuous column of liquid while passing throughthe microdialysis probe 12 and by means of a connecting line 22 throughthe test cell 14 into a collecting vessel 24. This pumping isimplemented by a two-channel roller metering pump 26 inserted into theconnecting line 22. The second channel of the roller metering pump 26 isloaded at its intake side through a line 28 with an enzyme solution 30which is fed at its outlet side at a mixing station 32 into theconnecting line 22.

When the perfusion solution 18 flows through the microdialysis probe 12,a glucose diffusion exchange takes place at the glucose-permeabledialysis membrane 34 between the perfusion liquid and the tissue liquid.Depending on the concentration gradient, the perfusion solution 18flowing past the membrane 14 is enriched with tissue glucose. Thereuponthe glucose content of the perfusion solution is determined in knownmanner, using an electrochemical/amperometric sensor, in the test cell14, as an electrode signal and is analyzed in the signal processing unit16. The basic detection reactions catalyzed by the enzyme solution 30are described in detail in the German Offenlegungsschrift 44 01 400, andare explicitly referred to herewith. In an alternative, the glucose alsomay be detected using an enzyme sensor as described in the GermanOffenlegungsschrift 41 30 742.

The conveyance of the perfusion solution 18 through the pump 26 iscarried out in the invention at predetermined time intervals in themanner shown in FIG. 2. The perfusion solution is moved during adialysis interval T₁ at several mutually distinct and consecutive timesin conveyed batches 36, each conveyed batch 36 correspondingsubstantially to the volumetric content of the microdialysis probe 12.The conveyance pauses 38 between the conveyed batches 36 are selected insuch manner that the glucose content of the particular volume ofperfusion solution 18 in the microdialysis probe 12 substantially equalsthe tissue glucose concentration. In principle the volumetric flow ofthe perfusion solution 18 also may be reduced to a constant value dV₀/dt for the duration of the dialysis interval, whereby the transmittedquantity of perfusion solution 18 during the time interval T₁corresponds to that of the batch conveyance. However the pump 26 thenmust be adjustable in its flow.

The volume of perfusion solution 18 enriched in the probe 12 during theinterval T₁ is pumped during the course of the ensuing transportinterval T₂ at a constant volumetric flow dV₁ /dt determined by the flowoutput of the pump 26 into the test cell 14. On account of the higherspeed of flow, the trailing perfusion solution 18 flowing in this phasethrough the microdialysis probe 12 is hardly laden with glucose from thetissue 10. Therefore the test signal from the test cell presents a peakvalue when the enriched segments of the liquid column are moved past andit will show a base line value when liquid volumes passing through theprobe 12 with short durations of perfusion are being transported.Accordingly the base lines and the extrema can be measured atpredetermined times within the total time interval T₁ +T₂. Typicalconveyance flows are 0.3-1 μltr/min for T₁ and 5-50 μltr/min for T₂.

Improved analysis, in particular regarding signal drift and validity, isimplemented in that the perfusion solution 18 in the reservoir 20 ismixed with glucose. The initial concentration within the physiologicalrange is set for instance at 5 mmole/ltr. Alternatively however, theglucose solution can be prepared separately from the perfusion solution20 in separate glucose reservoirs appropriately and selectivelycommunicating through switching valves with the perfusate line 21.

If the test sensor is linear, tissue glucose can be ascertained by thefact that the ratio of the extremum detected during the interval to theassociated base line value is multiplied by the value of the initialglucose concentration and where called for by a calibration factor. Thecalibration factor can be determined by a one-time in-vivo comparisonmeasurement of the glucose levels in the blood and in the tissue.Appropriately an offset ascertained by a one-time in-vitro measurementbefore implantation while dipping the probe 12 into a glucose-free testsolution shall be taken into account. Adding glucose to the perfusionsolution 18 therefore allows automatically recalibrating the testsignals once an initial calibration was carried out.

Signal validity can be monitored merely by pattern recognition. A peakis obtained when comparing a glucose content of the tissue 10 which ishigher than the adjusted concentration, and a dip if the glucose contentis lower. Illustratively a signal shape which deviates because of zeroshift can be detected in this manner as being invalid. In this manner itis possible also to monitor a patient's glucose level within apredetermined range by means of simple qualitative comparisonmeasurements. For instance the initial glucose concentration in theperfusion solution 30 may be alternatingly adjusted to asugar-deficiency value and to an excess sugar value, a warning signalbeing emitted for a dip in the sequence of the test signals during thephase adjusted sugar-deficiency concentration and for a peak during thephase of adjusted sugar-surplus concentration.

In this procedure, signal shape recognition is restricted to detectingtwo measurement values in each case, namely an extremum associated withthe high glucose yield during the dialysis interval T₁ and a base linevalue associated with the low glucose yield (because of the highvolumetric flow dV₁ /dt) during the transport intervals T₂. The twomeasurement values can be ascertained each at predetermined times withinthe time interval T₁ +T₂, a peak being as the signal shape whencomparing an extremum larger than the base line value, and a dip beingassumed when comparing an extremum smaller than the base line value.

In summary, the invention relates to a method and apparatus fordetermining tissue glucose, a perfusion solution being moved as a liquidcolumn to pass through a microdialysis probe implanted in the tissue toa test cell. In order to increase yield, to avert concentrationgradients and to reduce the dead time, the invention proposes that thevolumetric flow V of the perfusion solution over the duration of thedialysis intervals T₁ be reduced to a time-averaged value of dV₀ /dt andthat the volume of the perfusion solution which is perfused through themicrodialysis probe during each dialysis interval T₁ be moved in eachensuing transport interval T₂ at a higher volumetric flow dV₁ /dt to thetest cell.

What is claimed is:
 1. Method for determining and monitoring tissueglucose concentration, wherein a perfusion solution (18) is conveyed asa liquid column through a microdialysis probe (12) implanted in thetissue (10) and is moved to a test cell (14) preferably arranged outsidethe patient's body, the volumetric flow of the perfusion solution (18)being reduced in its time average for the duration of the dialysisintervals (T₁) and the volume of the perfusion solution (18) perfusedthrough the microdialysis probe (12) during each dialysis interval (T₁)being moved on in a consecutive transport interval (T₂) at a highervolumetric flow to the test cell (14) and wherein the glucose content ofthe perfusion solution (18) passing through the test cell (14) isdetermined from continuously detected test signals,wherein beforepassing through the microdialysis probe (12) the perfusion solution (18)is mixed with glucose in order to set a predetermined initialconcentration.
 2. Method as claimed in claim 1, wherein the initialglucose concentration is set to be within the physiological range. 3.Method as claimed in claim 1, wherein the volumetric flow (dV₁ /dt) ofthe perfusion solution (18) is adjusted in such manner during thetransport intervals (T₂) that the glucose content of the perfusionsolution (18) changes less than 10%, preferably less than 5% when thesolution passes through the microdialysis probe (12).
 4. Method asclaimed in claim 1, wherein the volumetric flow (dV₀ /dt) of theperfusion solution is adjusted in such manner during the dialysisintervals (T₁) that the glucose content of the perfusion solution (18)as it passes through the microdialysis probe (12) substantially equalsthe tissue glucose concentration.
 5. Method as claimed in claim 1,wherein a base line value is determined from test signals picked up atthe test cell (14) during the flow-through of the volume of theperfusion solution (18) perfused at the higher volumetric flow (dV₁/dt).
 6. Method as claimed in claim 1, wherein the concentration of thetissue glucose is determined from the extremum or from the integralvalue of the test signals detected at the test cell (14) during eachtransport interval (T₂).
 7. Method as claimed in claim 5, wherein theratio of extremum to base line value of the peak- or dip-shaped signalsequence of the test signals is formed and is multiplied by the value ofthe initial glucose concentration and if necessary by a predeterminedcalibration factor to determine the tissue glucose concentration. 8.Method as claimed in claim 6, wherein the time separation of the extremaof the measurement values predetermined by the time interval (T₁ +T₂) ofthe transport intervals T₂ is monitored to check the validity of thetest signals.
 9. Method as claimed in claim 2, wherein the signalsequence of the test signals detected during each transport interval(T₂) at the test cell (14) is analyzed to check the validity of thedetermined glucose content, a peak being expected as a valid signalshape when the concentration value is higher than the adjusted initialglucose concentration and a dip being expected for a lesserconcentration.
 10. Method as claimed in claim 2, wherein the initialglucose concentration is set at a sugar-deficiency value and that upon adip in the sequence of the test signals a sugar-deficiency alarm isemitted.
 11. Method as claimed in claim 2, wherein the initial glucoseconcentration is set in alternating phases to a sugar-deficiency valueand to a sugar-excess value and that, upon a dip in the sequence of thetest signals during the phase set to sugar-deficiency concentration, andupon a peak of the phase set to excess-sugar concentration, an alarmsignal is emitted.
 12. Method as claimed in claim 1, wherein the extremadetermined in the time interval (T₁ +T₂) of the transport intervals (T₂)are compared with the particular associated base line value to achievequalitative pattern recognition of the sequence of the test signals, apeak being recognized as a signal shape when the extremum compared thethe base line value is larger and a dip when the extremum is smaller.13. Method as claimed in claim 1, wherein during each dialysis interval(T₁) the perfusion solution (18) is moved in several batches (36)mutually apart by a time interval (38) through the microdialysis probe(12).
 14. Method as claimed in claim 13, wherein at each batch (36) avolume of the perfusion solution (18) essentially corresponding to thecontent of the microdialysis probe (12) is moved on.